Parkinson's disease (PD) is the second most common neurodegenerative disease with more than 1 million affected in the United States, and yet treatment of PD has proved difficult. Neurotrophic factors (NTF) have been attractive treatments for PD as they target the survival and maintenance of existing neurons rather than providing pharmacological stimulation. However, conflicting findings regarding their efficacy and concern about clinical issues have been significant drawbacks for further clinical development of NTFs such as GDNF and BDNF. Recently, a novel family of NTFs has been identified which includes cerebral dopamine neurotrophic factor (CDNF). CDNF, a dopamine-specific NTF, is a small molecule that appears to be more bioavailable than GDNF. While initial studies in rodents have indicated great promise for the therapeutic value of CDNF, its efficacy has not been studied in a primate species - a crucial step for the translation of its effects into the potential development of clinical trials. Additionally, most PD research in both humans and animal models, including that of CDNF, has focused on the motor symptoms of PD, yet given that the majority of PD patients cite the non-motor symptoms (NMS) of PD as the most debilitating to quality of life, investigating novel treatments geared toward slowing the progression of NMS symptoms is urgently needed. This study will determine in a monkey model whether a treatment with CDNF after MPTP exposure will provide therapy against the DA neuron loss and motor and non-motor deficits associated with PD. Monkeys will be given a small intra-carotid dose of MPTP, followed by treatment with either CDNF (450[unreadable]g or 125[unreadable]g) or GDNF (450[unreadable]g) or vehicle at 3, 4, 5 and 6 months post-MPTP. Aim 1 will determine how well CDNF protects against the progression of motor deficits induced by MPTP by analyzing gross and fine motor skills in the home pen setting, on the Automated Movement Tracking system, on the monkey Motor Assessment Panel, and on the monkey Parkinsonian Rating Scale before and after MPTP exposure followed by NTF treatment. Aim 2 will determine whether CDNF is effective in treating the cognitive declines commonly observed in the early stages of PD by analyzing monkeys'performance on the Cognitive Set Shifting Task (CSST). Aim 3 will examine the mechanism of therapy by quantifying via immunoblotting the striatal expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and vesicular monoamine transporter (VMAT2), proteins associated with DA neurons, as well as concentrations of DA and its metabolites, at the end of the study. For all measures, CDNF will be compared to GDNF, a well-studied NTF treatment for PD, and vehicle. Together, these experiments will test whether the novel trophic factor CDNF may provide a promising therapy to protect DA neurons from neurotoxic damage and reduce the motor and non-motor deficits characteristic of PD. PUBLIC HEALTH RELEVANCE: This proposal will utilize a rhesus monkey model to determine if treatment with a novel neurotrophic factor (NTF), CDNF, will counteract neurotoxic damage to the nigrostriatal dopaminergic neurons in a primate species, and thereby serve as a possible new therapy in the early stages of Parkinson's disease (PD). Understanding the cellular mechanisms by which CDNF is neuroprotective could also potentially help with the development of new pharmaceutical therapies for PD.